FDA Label for Baclofen

Boxed Warning

WARNING: DO NOT DISCONTINUE ABRUPTLY

Abrupt discontinuation of intrathecal baclofen, regardless of the cause, has resulted in sequelae that include high fever, altered mental status, exaggerated rebound spasticity, and muscle rigidity, that in rare cases has advanced to rhabdomyolysis, multiple organ-system failure and death.

Prevention of abrupt discontinuation of intrathecal baclofen requires careful attention to programming and monitoring of the infusion system, refill scheduling and procedures, and pump alarms. Patients and caregivers should be advised of the importance of keeping scheduled refill visits and should be educated on the early symptoms of baclofen withdrawal. Special attention should be given to patients at apparent risk (e.g., spinal cord injuries at T-6 or above, communication difficulties, history of withdrawal symptoms from oral or intrathecal baclofen). Consult the technical manual of the implantable infusion system for additional post-implant clinician and patient information [ see Warnings and Precautions (5.4)].

1 Indications And Usage

Baclofen injection is indicated for use in the management of severe spasticity in adult and pediatric patients age 4 years and above. Patients should first respond to a screening dose of intrathecal baclofen prior to consideration for long term infusion via an implantable pump. For spasticity of spinal cord origin, chronic infusion of baclofen injection via an implantable pump should be reserved for patients unresponsive to oral baclofen therapy, or those who experience intolerable CNS side effects at effective doses.

Patients with spasticity due to traumatic brain injury should wait at least one year after the injury before consideration of long term intrathecal baclofen therapy. Baclofen injection is intended for use by the intrathecal route in single bolus test doses (via spinal catheter or lumbar puncture) and, for chronic use, only with the Medtronic SynchroMed® II Programmable Pump or other pumps labeled for intrathecal administration of baclofen injection [see Clinical Studies (14)] .

Prior to implantation of a device for chronic intrathecal infusion of baclofen injection, patients must show a response to baclofen injection in a screening trial [see Dosage and Administration (2.2)] .

2 Dosage And Administration

3 Dosage Forms And Strengths

Baclofen injection is available, for intrathecal use only, in:

• Single-dose vials of 10,000 mcg per 20 mL (500 mcg/mL)
• Single-dose vials of 20,000 mcg per 20 mL (1,000 mcg/mL)
• Single-dose vials of 40,000 mcg per 20 mL (2,000 mcg/mL)

4 Contraindications

Baclofen injection is contraindicated in patients with a hypersensitivity to baclofen. Do not use baclofen injection for intravenous, intramuscular, subcutaneous or epidural administration.

5 Warnings And Precautions

7 Drug Interactions

There is inadequate systematic experience with the use of intrathecal baclofen in combination with other medications to predict specific drug-drug interactions. Interactions attributed to the combined use of baclofen injection and epidural morphine include hypotension and dyspnea.

8.1 Pregnancy

Risk Summary

There are no adequate data on the developmental risk associated with the use of baclofen injection in pregnant women.

In animal studies, oral administration of baclofen to pregnant rats produced an increase in fetal malformations (see Data). There are no animal data on developmental risk associated with baclofen administered via continuous intrathecal infusion.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Baclofen given orally to pregnant rats has been shown to increase the incidence of omphaloceles (ventral hernias) in fetuses at a dose associated with maternal toxicity. This abnormality was not seen in mice or rabbits.

8.2 Lactation

Risk Summary
There is insufficient information regarding levels of baclofen in milk of nursing mothers receiving baclofen injection. There are no adequate data on the effects of baclofen injection on the breastfed infant or on milk production. At recommended oral doses, baclofen is present in human milk and withdrawal symptoms can occur in breastfed infants when maternal administration of baclofen is stopped or when breastfeeding is stopped.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for baclofen injection and any potential adverse effects on the breastfed infant from baclofen injection or from the underlying maternal condition.

8.4 Pediatric Use

Children should be of sufficient body mass to accommodate the implantable pump for chronic infusion. Please consult pump manufacturer's manual for specific recommendations. Safety and effectiveness in pediatric patients below the age of 4 have not been established.

10 Overdosage

Special attention must be given to recognizing the signs and symptoms of overdosage, especially during the initial screening and dose-titration phase of treatment, but also during re-introduction of baclofen injection after a period of interruption in therapy.

Symptoms of Intrathecal Baclofen Overdose

Drowsiness, lightheadedness, dizziness, somnolence, respiratory depression, seizures, rostral progression of hypotonia and loss of consciousness progressing to coma of up to 72 hours duration. In most cases reported, coma was reversible without sequelae after drug was discontinued. Symptoms of intrathecal baclofen overdose were reported in a sensitive adult patient after receiving a 25 mcg intrathecal bolus.

Treatment Suggestions for Overdose

There is no specific antidote for treating overdoses of baclofen injection; however, the following steps should ordinarily be undertaken:

1) Residual intrathecal baclofen solution should be removed from the pump as soon as possible.

2) Patients with respiratory depression should be intubated if necessary, until the drug is eliminated.

Anecdotal reports suggest that intravenous physostigmine may reverse central side effects, notably drowsiness and respiratory depression. Caution in administering physostigmine is advised, however, because its use has been associated with the induction of seizures and bradycardia.

Physostigmine Doses for Adult Patients

Administer 2 mg of physostigmine intramuscularly or intravenously at a slow controlled rate of no more than 1 mg per minute. Dosage may be repeated if life-threatening signs, such as arrhythmia, convulsions or coma occur.

Physostigmine Doses for Pediatric Patients

Administer 0.02 mg/kg physostigmine intramuscularly or intravenously, do not give more than 0.5 mg per minute. The dosage may be repeated at 5 to 10 minute intervals until a therapeutic effect is obtained or a maximum dose of 2 mg is attained.

Physostigmine may not be effective in reversing large overdoses and patients may need to be maintained with respiratory support.

If lumbar puncture is not contraindicated, consideration should be given to withdrawing 30 to 40 mL of CSF to reduce CSF baclofen concentration.

11 Description

Baclofen injection is a muscle relaxant and antispastic. Baclofen's pharmacological class is a gamma-aminobutyric acid (GABA)ergic agonist. Baclofen's chemical name is 4-amino- 3-(4-chlorophenyl) butanoic acid, and its structural formula is:

Baclofen

Baclofen Injection Structure - baclofen injection structure

C ₁₀H ₁₂ClNO ₂

Baclofen is a white to off-white powder, with a molecular weight of 213.66. It is slightly soluble in water, very slightly soluble in methanol and ethanol, practically insoluble in acetone and ether, soluble in 0.1N hydrochloric acid, 0.1N sodium hydroxide, and insoluble in chloroform.

Baclofen injection is a sterile, pyrogen-free, isotonic solution free of antioxidants, preservatives or other potentially neurotoxic additives indicated only for intrathecal administration. The drug is stable in solution at 37°C and compatible with CSF. Each mL of baclofen injection contains baclofen USP 500 mcg, 1,000 mcg or 2,000 mcg and sodium chloride 9 mg in Water for Injection; pH range is 5.5 to 7.5.

12.1 Mechanism Of Action

The precise mechanism of action of baclofen as a muscle relaxant and antispasticity agent is not fully understood. Baclofen inhibits both monosynaptic and polysynaptic reflexes at the spinal level, possibly by decreasing excitatory neurotransmitter release from primary afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect. Baclofen is a structural analog of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and may exert its effects by stimulation of the GABAB receptor subtype. 

Baclofen when introduced directly into the intrathecal space permits effective CSF concentrations to be achieved with resultant plasma concentrations 100 times less than those occurring with oral administration. In people, as well as in animals, baclofen has been shown to have general CNS depressant properties as indicated by the production of sedation with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression. 

12.2 Pharmacodynamics

Intrathecal Bolus

Adult Patients 
The onset of action is generally one-half hour to one hour after an intrathecal bolus. Peak spasmolytic effect is seen at approximately four hours after dosing and effects may last four to eight hours. Onset, peak response, and duration of action may vary with individual patients depending on the dose and severity of symptoms. 

Pediatric Patients 
The onset, peak response and duration of action are similar to those seen in adult patients. 

Continuous Infusion

Adult Patients 
Intrathecal baclofen's antispastic action is first seen at 6 to 8 hours after initiation of continuous infusion. Maximum activity is observed in 24 to 48 hours. 

Pediatric Patients 
No additional information on continuous infusions is available for pediatric patients. 

12.3 Pharmacokinetics

The pharmacokinetics of cerebrospinal fluid (CSF) clearance of intrathecal baclofen calculated from intrathecal bolus or continuous infusion studies approximates CSF turnover, suggesting elimination is by bulk-flow removal of CSF. 

Intrathecal Bolus 
After a bolus lumbar injection of 50 mcg or 100 mcg intrathecal baclofen in seven patients, the average CSF elimination half-life was 1.51 hours over the first four hours and the average CSF clearance was approximately 30 mL/hour. 

Continuous Infusion 
The mean CSF clearance for intrathecal baclofen was approximately 30 mL/hour in a study involving ten patients on continuous intrathecal infusion. Concurrent plasma concentrations of baclofen during intrathecal administration are expected to be low (0 to 5 ng/mL). Limited pharmacokinetic data suggest that a lumbar-cisternal concentration gradient of about 4:1 is established along the neuroaxis during baclofen infusion. This is based upon simultaneous CSF sampling via cisternal and lumbar tap in 5 patients receiving continuous baclofen infusion at the lumbar level at doses associated with therapeutic efficacy; the interpatient variability was great. The gradient was not altered by position. Six pediatric patients (age 8 to 18 years) receiving continuous intrathecal baclofen infusion at doses of 77 to 400 mcg/day had plasma baclofen levels near or below 10 ng/mL. 

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

No increase in tumors was seen in rats receiving baclofen orally for two years.

Mutagenesis

Mutagenicity assays with baclofen have not been performed.

Impairment of Fertility

Studies to assess the potential for adverse effects of baclofen on fertility have not been conducted.

14 Clinical Studies

Spasticity of Spinal Cord Origin 
Evidence supporting the efficacy of intrathecal baclofen was obtained in randomized, controlled investigations that compared the effects of either a single intrathecal dose or a three day intrathecal infusion of intrathecal baclofen to placebo in patients with severe spasticity and spasms due to either spinal cord trauma or multiple sclerosis. Intrathecal baclofen was superior to placebo on both principal outcome measures employed: change from baseline in the Ashworth rating of spasticity and the frequency of spasms. 

Spasticity of Cerebral Origin 
The efficacy of intrathecal baclofen was investigated in three controlled clinical trials; two enrolled patients with cerebral palsy and one enrolled patients with spasticity due to previous brain injury.

The first study, a randomized controlled cross-over trial of 51 patients with cerebral palsy, provided strong, statistically significant results; intrathecal baclofen was superior to placebo in reducing spasticity as measured by the Ashworth Scale. A second cross-over study was conducted in 11 patients with spasticity arising from brain injury. Despite the small sample size, the study yielded a nearly significant test statistic (p=0.066) and provided directionally favorable results. The last study, however, did not provide data that could be reliably analyzed. 

16 How Supplied/Storage And Handling

Baclofen injection, USP is a sterile, pyrogen-free, isotonic solution available in single-dose vials of 10,000 mcg per 20 mL (500 mcg/mL), 20,000 mcg per 20 mL (1,000 mcg/mL), and 40,000 mcg per 20 mL (2,000 mcg/mL) for intrathecal administration only.

500 mcg per mL

NDC 72888-145-36: 20 mL Vial - 10,000 mcg per 20 mL

1,000 mcg per mL

NDC 72888-146-36: 20 mL Vial - 20,000 mcg per 20 mL

2,000 mcg per mL

NDC 72888-147-36: 20 mL Vial - 40,000 mcg per 20 mL

Baclofen injection does not contain any antioxidants, preservatives or other potentially neurotoxic additives. Each single-dose vial is intended for single use only.

Discard any unused portion.

Does not require refrigeration.

Do not store above 86°F (30°C).

Do not freeze.

Do not heat sterilize.

17 Patient Counseling Information

Risks Related to Sudden Withdrawal of Baclofen Injection

Advise patients and caregivers that sudden withdrawal of baclofen injection, regardless of the cause, can result in serious complications that include high fever, confusion, muscle stiffness, multiple organ-system failure, and death. Inform patients that early symptoms of baclofen injection withdrawal may include increased spasticity, itching, and tingling of extremities. If baclofen injection withdrawal or a pump malfunction is suspected, patients should be brought immediately to a hospital for assessment and treatment.

Inform patients and caregivers that sudden withdrawal occurs most frequently due to a delivery problem with the catheter or the pump, or failure to refill the pump on schedule. Advise patients and their caregivers to pay careful attention to infusion system alarms. Instruct patients and caregivers that if they miss their scheduled pump refill, they should immediately contact their physician to reschedule the refill before the pump runs out of drug.

Baclofen Injection Overdose

Inform patients and their caregivers that baclofen injection overdose may occur suddenly or insidiously, and that symptoms may include confusion, drowsiness, lightheadedness, dizziness, slow or shallow breathing, seizures, loss of muscle tone, loss of consciousness, and coma. If an overdose appears likely, patients should be brought immediately to a hospital for assessment and possible emptying of the pump.

Operation of Automobiles and Other Dangerous Machinery

Advise patients that baclofen injection may cause drowsiness, and that they should exercise caution regarding the operation of automobiles or other dangerous machinery, or activities made hazardous by decreased alertness.

Increased Risk of Drowsiness with Alcohol and Other CNS Depressants

Inform patients and their caregivers that the drowsiness associated with baclofen injection use can be worsened by alcohol and other CNS depressants. Advise patients to read all medicine labels carefully, and to tell their physician about all prescription and nonprescription drugs they may use.

Distributed by:

Advagen Pharma Ltd

666 Plainsboro Road

Suite 605 Plainsboro, NJ 08536, USA.

Revision: 02/2023

Package Label-Principal Display Panel

Baclofen Injection 500 mcg per mL - NDC 72888-145-36 - Single-Dose Vial Label

Baclofen Injection 500 mcg per mL - NDC 72888-145-36 - Single-Dose Vial Label - baclofen injection 500mcg label

Baclofen Injection 500 mcg per mL - NDC 72888-145-36 - Single-Dose Vial Carton Label

Baclofen Injection 1,000 mcg per mL - NDC 72888-146-36 - Single-Dose Vial Label

Baclofen Injection 1,000 mcg per mL - NDC 72888-146-36 - Single-Dose Vial Carton Label

Baclofen Injection 2,000 mcg per mL - NDC 72888-147-36 - Single-Dose Vial Label

Baclofen Injection 2,000 mcg per mL - NDC 72888-147-36 - Single-Dose Vial Carton Label